JP3296437B2 - N-substituted indole-3-glyoxylamides having anti-asthma, anti-allergic and immunosuppressive / immunomodulatory effects - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Indole-3-glyoxylamide is widely used as a pharmacodynamically active compound and as a synthetic building block in drug chemistry.

The Dutch patent application NL6502481 describes compounds with anti-inflammatory and antipyretic profile and analgesic action.

UK Patent Application GB-PS 1028812 includes Indolyl-3
-Derivatives of glyoxylic acid and amides thereof are described as compounds having analgesic, antispasmodic and β-adrenergic action.

G. Domschke et al. (Ber. 94, 2353 (196
1)) describes 3-indolyl-glyoxylamides, but they have not been pharmacologically characterized.

E. Walton et al., J. Med. Chem. 11, 1252 (196
8) reported indolyl-3-glyoxylic acid-derivatives and reported that they inhibited glycerophosphate-dehydrogenase and lactate-dehydrogenase.

European Patent Specification EP 0675110 A1 describes 1H-indole-3-glyoxylic amides, which are described as sPLA2-inhibitors, for the treatment of septic shock, pancreatitis, allergic rhinitis and rheumatism. Used in the treatment of osteoarthritis.

It is an object of the present invention to provide new compounds from the indolyl-3-glyoxylic acid system having anti-asthmatic and immunomodulatory effects.

In addition, the chemical preparation of these compounds and the pharmaceutical processes for converting the novel compounds into pharmaceuticals and their application forms are described.

The object of the present invention is a compound of general formula I: Wherein the groups R, R ₁ , R ₂ , R ₃ , R ₄ and Z have the following meanings: R represents hydrogen, C ₁ -C ₆ -alkyl, wherein the alkyl group is a phenyl ring 1 May be replaced by more than one. This phenyl ring itself also has one or more halogens,
C ₁ -C ₆ - alkyl, C ₃ -C ₇ - by cycloalkyl, by carboxyl groups, C ₁ -C ₆ - alkanol esterified carboxyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group Benzyloxy group and in the phenyl moiety by a benzyl group substituted by one or more C ₁ -C ₆ -alkyl groups, halogen atoms or trifluoromethyl groups.

R ₁ is one or more C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy, benzyloxy, nitro, amino, C ₁
-C ₆ - alkylamino, C ₁ -C ₆ - alkoxycarbonylamino and or C ₁ -C a carboxyl group ₆ - phenyl ring is substituted by esterified carboxyl group alkanol or formula II: Where the pyridine-
Skeleton is bound selectively in ring carbon atoms 2, 3 and 4 may be substituted by substituents R ₅ and R _6. R ₅ and
R ₆ may be the same or different, C ₁ -C ₆ - alkyl, C ₃ -C ₇ - cycloalkyl, C ₁ -C ₆ - alkoxy,
Stands for nitro, amino, hydroxy, halogen and trifluoromethyl, further for ethoxycarbonylamino and carboxyalkoxy, wherein the alkyl group may have 1 to 4 C-atoms.

R ₁ may further be a 2- or 4-pyrimidinyl-heterocycle or a pyridylmethyl-group, wherein CH ₂ is 2
-, 3, may be present in the 4-position, the 2-pyrimidinyl - ring may be substituted with one or more methyl groups, further, C ₁ -C ₆ - alkyl, halogen, nitro group, 2 substituted with an amino group and a C ₁ -C ₆ -alkylamino group
Represents a-, 3- and 4-quinolyl skeleton, and represents a 2-, 3- and 4-quinolylmethyl group, wherein the ring carbons of the pyridylmethyl- and quinolylmethyl- groups are C ₁ -C ₆ -alkyl, C _1- C ₆ - alkoxy, nitro, amino and C ₁ -C ₆ -
It may be substituted by alkoxycarbonylamino.

When R represents hydrogen or a benzyl group, R ₁ further comprises:
Acid residues of natural or unnatural amino acids, such as α-glycyl-, α-sarcosyl-, α-alanyl-, α-leucyl-, α-iso-leucyl-, α-seryl-, α-phenylalanyl- , Α-histidyl-, α-prolyl-,
α-arginyl-, α-lysyl-, α-asparagyl-
And α-glutamyl group, wherein the amino group of each amino acid may be present unprotected or protected. Carbobenzoxy groups (Z-groups) and t-butoxycarbonyl groups (BOC-groups) and acetyl groups correspond to protective groups for amino functions. R ₁
In the case of the asparagyl- and glutamyl groups claimed as:
As free carboxyl groups or in the form of esters with C ₁ -C ₆ -alkanols, for example methyl-, ethyl- or t-
-Exists as a butyl ester. Further, R ₁ may represent an allylaminocarbonyl-2-methyl-prop-1-yl group. Further, when R ₁ represents an aminoalkylene group, R and R ₁ may further form a piperazine ring or a homopiperazine ring of the formula III together with the nitrogen atom bonded thereto. , Wherein R ₇ is an alkyl group, one or more C ₁ -C ₆ -alkyl, C ₁ -C ₆
Represents a phenyl ring which may be substituted by C ₁ -C ₆ -alkylamino, benzhydryl and bis-p-fluorobenzylhydryl by alkoxy, halogen, nitro and amino functions. R ₂ may represent hydrogen or a C ₁ -C ₆ -alkyl-group, wherein the alkyl group is substituted by one or more halogen and phenyl, and phenyl itself may also contain one or more halogen, C ₁ -C ₆ - alkyl, C ₃ -C ₇ - cycloalkyl, carboxyl group, C ₁ -C ₆
It may be substituted by carboxyl, trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy groups esterified with alkanols. The C ₁ -C ₆ -alkyl group corresponding to R ₂ may be further substituted by a 2-quinolyl group and 2-, 3- and 4-pyridyl skeletons, each of which may have one or more halogens. , C ₁ ~C ₄ - alkyl or C ₁ -C ₄ - it may be substituted by an alkoxy group. Furthermore, R ₂ represents an aroyl group, wherein the aryl moiety on which the group is based is one or more of halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₇
- expressed alkanol esterified carboxyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, an may phenyl ring substituted by an ethoxy group or a benzyl group - a cycloalkyl, carboxyl group, C ₁ -C _6.

R ₃ and R ₄ can be the same or different and include hydrogen, hydroxy, C ₁ -C ₆ -alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkanoyl, C ₁ -C ₆ -Alkoxy,
Represents halogen and benzyloxy. R ₃ and R4 further nitro group, an amino group, C ₁ -C ₄ - mono- - or dialkyl-substituted amino group and C ₁ -C ₃ - alkoxy - carbonylamino -
Functional groups or C ₁ -C ₃ - alkoxycarbonylamino -C ₁ ~
C ₃ - alkyl - may represent a functional group.

Z represents O or S.

The description of the radicals R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ Alkyl-, alkanol-, alkoxy- or alkylamino groups are usually “linear” or “branched” It should be understood that the "linear alkyl group" is, for example, methyl, ethyl, n-propyl, n-
It can mean butyl, n-pentyl, n-hexyl, and "branched alkyl group" means a group such as, for example, isopropyl or t-butyl. "Cycloalkyl"
Is to be understood, for example, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

"Halogen" is fluorine, chlorine, bromine or iodine.
"Alkoxy group" means, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.

Compounds of the present invention, as acid addition salts, for example, inorganic acids,
For example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, organic acids such as salts of acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, trifluoroacetic acid and succinic acid May also exist.

Both the compounds of formula I and their salts are biologically active. The compounds of the formula I can be applied in free form or as salts with physiologically tolerable acids.

Application can be oral, parenteral, intravenous, transdermal, or by inhalation.

The present invention furthermore relates to compounds of the formula I or their salts with physiologically tolerable inorganic or organic acids and optionally pharmaceutically usable carriers and / or diluents or auxiliaries. Pharmaceutical compositions containing the same.

Applicable forms include, for example, tablets, sugar-coated pills, capsules,
Solutions or ampules, suppositories, plasters, inhalable powder applications, suspensions, creams and ointments are preferred.

The compounds of the invention show good anti-asthma, anti-allergic and immunosuppressive / immunomodulatory effects in the following pharmacological models, for example at the time of transplantation and in diseases such as psoriasis, rheumatic diseases and chronic polyarthritis: "Late-phase" in the BAL for 24 hours after allergen challenge in guinea pigs-suppression of eosinophilia Male guinea pigs (200-250 g, Dunkin Hartley Shoe) were injected intraperitoneally with ovalbumin (ovalbumin 10 μg + Al ( OH)
₃₁ mg) and boosted 2 weeks later. One week after the ovalbumin booster administration, the animals were challenged with ovalbumin (0.5% solution) by inhalation for 20-30 seconds. Twenty-four hours later, the animals were sacrificed by urethane overdose, blood was removed and 0.9% saline 2
Bronchial cell irrigation (BAL) was performed with × 5 ml.

Collect the irrigation fluid, centrifuge at 400 g for 10 minutes, and remove the pellet.
It was suspended in 1 ml of 0.9% physiological saline. Becton Dickinson Testkit
After staining with No. 5877, eosinophils were counted microscopically in the Neubauer chamber. This test kit contains phloxin B as a selective dye for eosinophils. At this time, eosinophils in BAL were measured for each animal and expressed as eosinophils (million / animal). For each group, the mean and standard deviation were measured. The inhibition rate (%) of eosinophilia in the group treated with the test substance was calculated according to the following formula: (AB)-(BC) / (AC) × 100 = inhibition rate ( %) At this time, A corresponds to the eosinophils in the untreated challenge group, B corresponds to the eosinophils in the treated group, and C corresponds to the eosinophils in the non-challenged control group.

To avoid death, animals were treated with a histamine H1-antagonist (azelastine; 0.01 mg / kg, 2 hours before allergen challenge).
Oral). Application of test substances or vehicle was performed 4 hours after allergen challenge. The percent inhibition of eosinophilia in BAL was calculated in groups of 6-10 animals.

Assay for Measurement of Peptidyl Prolyl Isomerase (PPase) -Activity and Inhibition The PPase-activity of cyclophilin was measured enzymatically by the method of Fischer et al. (1984). After isomerization of the substrate by peptidylprolyl isomerase, it becomes reactive with chymotrypsin, which degrades the chromophore p-nitroaniline. Recombinant human CypB was used to measure inhibition of PPase activity by the substrate. The interaction of Cyp B with potential inhibitors was carried out as follows: Purified Cyp B at specific concentrations was added together with 1 μM substance for 1 μM.
Incubated for 5 minutes. Substrate solution in HEPES-buffer,
The PPase-reaction was initiated by addition to the reaction mixture containing chymotrypsin and the test- or control sample. Under these conditions, one-dimensional kinetics with constant K _observation = K ₀ + K _enz (where K ₀ is the spontaneous isomerization and _Kenz is the rate of isomerization of _PPase- activity) was gotten. The absorbance value corresponding to the amount of the decomposed chromophore,
Measurements were made at a constant reaction temperature of 10 ° C. using a Beckman DU70 spectral photometer. The residual activity observed in the presence of various substances was compared to cyclophilin treated with solvent only. The results were reported as residual activity (%). Cyclosporin A (CsA) was used as a reference compound. In addition, P by SDS-PAGE
Inhibition of Pase-activity was contrasted.

Colorimetric assay for non-radioactive quantification of cell proliferation and viability (based on MTT-test) Growth factors and cytokines such as IL-2 and IL-4
MTT is used for quantitative measurement of cell proliferation and activation during the up reaction and for quantification of antiproliferative or toxic effects.

This assay is based on the degradation of the yellow tetrazolium salt MTT by metabolically active cells into purple-red formazan crystals.

Cells cultured in 96-well tissue culture plates are
Incubate with the MTT-solution for about 4 hours. After this incubation time, purple-red formazan salt crystals form. This salt crystal is insoluble in the aqueous solution,
Dissolution can be achieved by the addition of a dissolution aid and by overnight incubation of the plate.

This dissolved formazan is quantified on a spectral photometer using an ELISA-reader. An increase in the number of surviving cells results in an increase in the total metabolic activity in the sample. This increase correlates directly with the amount of purple-red formazan crystals formed as measured by absorption.

The preparation of the compounds of the present invention is described in the following Schemes 1 and 2 and general procedures. All compounds can be prepared as described or analogously.

Compounds of general formula I are obtained according to the following scheme 1, shown in the structure of the compound of example 1: General Procedure for the Preparation of Compounds of the General Formula I According to Scheme 1 Step 1 An indole derivative, unsubstituted or optionally having one or more substituents in the C-2 or phenyl skeleton, is converted to a proton , Dipolar, aprotic or non-polar organic solvent,
For example isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dissolved N- methylpyrrolidone, dioxane, in toluene or methylene chloride, in the 3-necked flask N ₂ -
Drops are added to the suspension used in a molar amount or in excess of a base, such as sodium hydride, potassium hydroxide, potassium tert-butylate, dimethylaminopyridine or sodium amide, in a suitable solvent prepared under an atmosphere. Add.
Then, for example, the desired alkyl-, aralkyl- or heteroaralkylhalogenide is added, optionally with the addition of a catalyst such as copper, and allowed to react for a while, for example 30 minutes to 12 hours, at a temperature of 0 to 120 ° C., advantageously 30 ~ 80 ℃, especially 50
Keep within ~ 65 ° C. After the end of the reaction, the reaction mixture is taken up in water, the solution is extracted with, for example, diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether or tetrahydrofuran, and the organic phase obtained in each case is dried over anhydrous sodium sulphate.
The organic phase is concentrated in vacuo and the remaining residue is crystallized by friction or the oily residue is purified by recrystallization, distillation or column- or flash-chromatography on silica gel or aluminum oxide. The eluent used is, for example, a mixture of dichloromethane and diethyl ether in a ratio of 8: 2 (vol / vol) or a mixture of dichloromethane and ethanol in a ratio of 9: 1 (vol / vol).

Step 2 The N-substituted indole obtained by the above-mentioned operation of Step 1 is subjected to an aprotic or non-polar organic solvent such as diethyl ether, methyl-t-butyl ether, tetrahydrofuran, dioxane under a nitrogen atmosphere. toluene,
Dissolve in xylene, methylene chloride or chloroform,
An aprotic or non-polar solvent prepared under a nitrogen atmosphere, such as diethyl ether, methyl-t-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform in a molar excess of 60 to 60%. To a solution of oxalyl chloride at a temperature of -5 ° C to 20 ° C. The reaction solution is then heated at a temperature of from 10 to 130 ° C., preferably from 20 to 80 ° C., in particular from 30 to 50 ° C., for a period of from 30 minutes to 5 hours, followed by distilling off the solvent. The residue of indolyl-3-glyoxylic acid chloride formed in this way is converted to an aprotic solvent such as tetrahydrofuran, dioxane, dimethyl ether, toluene or a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide or Dissolve in dimethyl sulfoxide, cool to a temperature of 10 to -15 ° C, preferably -5 to 0 ° C, and add a solution of a primary or secondary amine in diluent in the presence of an acid binder.

As the diluent, the solvent used for dissolving the above-mentioned indolyl-3-glyoxylic acid chloride is used. Acid binders include triethylamine, pyridine,
Dimethylaminopyridine, basic ion exchangers, sodium carbonate, potassium carbonate, powdered potassium hydroxide and primary or secondary amines used in excess for the reaction are used. The reaction is carried out at 0 ° C to 120 ° C, preferably at 20 to 80 ° C, especially
It is carried out at a temperature of 0-60 ° C. After a reaction time of 1 to 3 hours and standing at room temperature for 24 hours, the hydrochloride of the acid binder is filtered off, the filtrate is concentrated in vacuo and the residue is recrystallized from an organic solvent or silica gel or aluminum oxide. Purification by column chromatography on As an eluent, for example, a mixture of dichloromethane and ethanol (95:
5, volume / volume) mixture is used.

EXAMPLES The following compounds, whose respective chemical names are listed in the following list, were synthesized by the general procedure for the first step and the second step, which form the basis of the synthesis scheme 1.
Table 1 below gives the general formula I and the substituents R _{1 to} R ₄ and Z, the structures and the melting points of these compounds: Example 1 N- (pyridin-4-yl)-[1- (4- Fluorobenzyl) -indol-3-yl] -glyoxylamide First step Sodium hydride 2.6 in 100 ml of 1- (4-fluorobenzyl) -indole dimethyl sulfoxide
To a mixture of 4 g (0.11 mol, mineral oil suspension), a solution of 11.72 g (0.1 mol) of indole in 50 ml of dimethyl sulfoxide is added. Heat to 60 ° C for 1.5 hours, then cool,
15.9 g (0.11 mol) of 4-fluorobenzyl chloride are added dropwise. The solution is warmed to 60 ° C., left overnight, and then poured into 400 ml of water with stirring. Extract several times with a total of 150 ml of methylene chloride, dry the organic phase over anhydrous sodium sulphate, filter and concentrate the filtrate in vacuo. The residue is distilled under high vacuum: 21.0 g (96% of logic). Boiling point (0.
5mm): 140 ° C.

Step 2 To a solution of 2.25 ml of oxalyl chloride in 25 ml of N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide ether was added
℃ is and under N ₂ gas, in ether 25 ml 1-(4-fluorobenzyl) - To a solution dropwise indole 4.75 g (21.1 mmol). The mixture is refluxed for 2 hours, and then the solvent is distilled off. Then 50 ml of tetrahydrofuran are added to the residue, the solution is cooled to -5 DEG C. and a solution of 4.66 g (49.5 mmol) of 4-aminopyridine in 200 ml of THF is added dropwise.
Heat to reflux for 3 hours and leave at room temperature overnight. The 4-aminopyridine hydrochloride is filtered off with suction, the precipitate is washed with THF, the filtrate is concentrated in vacuo and the residue is recrystallized from acetate.

Yield: 7.09 g (90% of theoretical), Melting point: 225-226 ° C Elemental analysis: Calculated. C70.77 H4.32 N11.25 Found. C71.09 H4.36 N11.26 Example 2: N- (Vyridin-4-yl)-(1-methyl-indol-3-yl) -glyoxylamide, Example 3: N- (pyridin-3-yl)-[1- (4-fluorobenzyl) -indole-3- Yl] -glyoxylamide, Example 4: N- (pyridin-3-yl)-(1-benzylindol-3-yl) -glyoxylamide, Example 5: N- (pyridin-3-yl)-[1- ( 2-Chlorobenzyl) -indol-3-yl] -glyoxylamide, Example 6: N- (4-fluorophenyl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide, Example 7 : N- (4-nitrophenyl)-[1- (4-fluorobenzyl) -indole-3- Le - glyoxylamide, Example 8: N- (2- chloropyridin-3-yl) - [1-
(4-Fluorobenzyl) -indol-3-yl]-
Glyoxylamide, Example 9: N- (pyridin-4-yl)-(1-benzylindol-3-yl) -glyoxylamide, Example 10: N- (pyridin-4-yl)-[1- (3-pyridyl) Methyl) -indol-3-yl] -glyoxylamide, Example 11: N- (4-fluorophenyl)-[1- (2-pyridylmethyl) -indol-3-yl] -glyoxylamide, Example 12: N- (4-Fluorophenyl)-[1- (3-pyridylmethyl) -indol-3-yl] -glyoxylamide, Example 13: N- (pyridin-4-yl)-[1- (4-chlorobenzyl)- Indol-3-yl] -glyoxylamide, Example 14: N- (pyridin-4-yl)-[1- (2-chlorobenzyl) -indol-3-yl] -glyoxylamide, Example 15: N- (pyridine -2-yl )-[1- (4-Fluorobenzyl) -indol-3-yl] -glyoxylamide, Example 16: N- (pyridin-4-yl)-[1- (2-pyridylmethyl) -indol-3-yl ] -Glyoxylamide, Example 17: (4-phenyl-piperazin-1-yl)-[1
-(4-Fluorobenzyl) -indol-3-yl]
Example 18: N- (pyridin-2-yl)-(1-benzyl-indol-3-yl) -glyoxylamide, Example 19: N- (pyridin-4-yl)-[1- (4 -Fluorobenzyl) -6-ethoxycarbonylamino-indol-3-yl] -glyoxylamide, Example 20: N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-ethoxycarbonylamino- Indole-3-yl] -glyoxylamide, Example 21: N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -6-cyclopentyloxycarbonylamino-indol-3-yl] -glyoxylamide, Example 22: 4- (pyridin-4-yl) -piperazin-1-yl)-[1- (4-fluorobenzyl) -indole-
3-yl] -glyoxylamide, Example 23: N- (3,4,5-trimethoxybenzyl) -N- (allylaminocarbonyl-2-methyl-prop-1-yl)-[1- (4-fluoro Benzyl) -indole-
3-yl] -glyoxylamide, Example 24: N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-methoxy-indol-3-yl]
Glyoxylamide, Example 25: N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl] -glyoxylamide, Example 26: N- (pyridin-4 -Yl)-[1- (4-Fluorobenzyl) -5-ethoxycarbonylamino-methyl-indol-3-yl] -glyoxylamide.

Starting Steps to Obtain Compounds of General Formula 1 Prepared According to Synthetic Scheme 1 (as Revealed in Table 1) All precursors for the synthetic steps of Examples 1-22 and 24-26 are: It is commercially available.

In addition, compounds of general formula 1 can also be obtained according to the synthetic route of scheme 2 described for the construction of compound 27: General Procedure for the Preparation of Compounds of the General Formula 1 According to Scheme 2 First Step: An aprotic or non-polar solvent, such as diethyl ether, methyl-t-butyl ether, prepared under a nitrogen atmosphere In a solution of oxalyl chloride in a molar excess of 1 to 60% in terahydrofuran, dioxane or dichloromethane at a temperature of -5 ° C to + 5 ° C, an indole derivative dissolved in said solvent for said oxalyl chloride ( This can be unsubstituted or substituted at C-2 or in the phenyl ring). The reaction solution is then heated to a temperature of from 10 to 120 ° C., preferably from 20 to 80 ° C., in particular from 30 to 60 ° C., for 1 to 5 hours, followed by distilling off the solvent. The remaining (indol-3-yl) glyoxylic chloride residue is dissolved in an aprotic solvent such as tetrahydrofuran, dioxane, diethyl ether, toluene or a dipolar and protic solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide. Or suspended, at a temperature between -10 ° C and + 10 ° C, preferably between -5 ° C and
Cool to 0 ° C. and add 1
Add a solution of the secondary or secondary amine. As a diluent, the solvent used for dissolving indolyl-3-glyoxylic acid chloride is used. As the acid binder, triethylamine, pyridine, dimethylaminopyridine, basic ion exchangers, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess primary or secondary amine used in the reaction are used. The reaction is carried out at 0-120 ° C,
It is preferably carried out at a temperature of from 20 to 80 ° C, in particular from 40 to 60 ° C. After a reaction time of 1-4 hours and standing at room temperature for 24 hours, filtration
The precipitate is digested with water, suction filtered and dried in vacuo.
The desired compound is purified by recrystallization in an organic solvent or by column chromatography on silica gel or aluminum oxide. As an eluent, for example, a mixture of dichloromethane and ethanol (10: 1 volume / volume) is used.

Second step: Indole obtained according to the procedure of the first step.
3-yl-glyoxylamide can be converted to a protic, dipolar, aprotic or non-polar organic solvent such as isopropanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethylacetamide,
N- methylpyrrolidone, dioxane, was dissolved in toluene or methylene chloride, N ₂ in Erlenmeyer flasks - base in a suitable solvent prepared under an atmosphere, such as sodium hydride, powdered potassium hydroxide, potassium -t- butylate ,
Add dropwise to the suspension used in molar amount or excess of dimethylaminopyridine or sodium amide. Then
The desired alkyl-, aralkyl- or heteroaralkylhalogenide can be used neat or, for example, indole-3.
In the diluent also used for dissolving the yl-glyoxylamide, optionally with the addition of a catalyst, for example copper, and reacting for a while, for example for 30 minutes to 12 hours,
It is maintained at a temperature in the range from 120 ° C, preferably from 30 to 80 ° C, especially from 50 to 70 ° C. After the end of the reaction, the reaction mixture is put into water and the solution is added, for example, diethyl ether, dichloromethane, chloroform, methyl-t-butyl ether,
Extraction is performed with tetrahydrofuran or n-butanol, and the obtained organic phases are dried over anhydrous sodium sulfate.

The organic phase is concentrated in vacuo and the remaining residue is crystallized by scraping or the oily residue is purified by distillation or column or flash chromatography on silica gel or aluminum oxide. As the eluent, for example, a mixture of methylene chloride and diethyl ether in a ratio of 8: 2 (vol / vol) or a mixture of methylene chloride and ethanol in a ratio of 9: 1 (vol / vol) is used.

Examples General operation method of the first step and the second step (Synthesis Reaction Scheme 2
Are based on the above), and the compounds shown in Table 1 were synthesized according to the synthesis process of Reaction Scheme 1.
Related precursors of these compounds are listed in Table 2.

Example 27 N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -indol-3-yl] glyoxylamide (final step, same as in Example 1) First step: N- (pyridin-4- Yl)-(indol-3-yl) glyoxylamide To a solution of 9 ml of oxalyl chloride in 100 ml of anhydrous ether,
At 0 ° C., a solution of 10 g (85.3 mmol) of indole in 100 ml of ether is added dropwise. The mixture is kept under reflux for 3 hours. Then, at -5 DEG C., a suspension of 12 g (127.9 mmol) of 4-aminopyridine in 500 ml of tetrahydrofuran is added dropwise, the reaction mixture is heated with stirring to reflux for 3 hours and left at room temperature overnight. Filter, treat the precipitate with water,
The dried compound is applied to a silica gel column (silica gel 60, Fa.M
erck AG, Darmstadt) through the eluent methylene chloride /
Purified using ethanol (10: 1, v / v).

Yield: 9.8 g (43.3% of theory) Melting point: 250 ° C or higher.

Second step: N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -3-yl] glyoxylamide N- (pyridin-4-yl) obtained in the first step
-Indol-3-yl) glyoxylamide is reacted with 4-fluorobenzyl chloride by a benzylation method (first step of Example 1), and the obtained compound is isolated.

Yield: 41% of theory Melting point: 224-225 ° C Elemental analysis: Calculated C70.77 H4.32 N11.25 Found C70.98 H4.40 N11.49 Example 28: N- (4-nitrophenyl) -[1- (4-Fluorobenzyl) -indol-3-yl] -glyoxylamide (final step, same as in Example 7).

Example 29: N- (4-Fluorophenyl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide (final step, same as Example 6).

Example 30: N- (pyridin-3-yl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide (final step, same as example 3).

According to Scheme 2 of the present invention, the following precursors (first step of Scheme 2, Table 2) were obtained: Example 31: N- (pyridin-4-yl)-(indole-3-
Ill) glyoxylamide Example 32: N- (4-nitrophenyl)-(indole-3-
Yl) glyoxylamide Example 33: N- (4-fluorophenyl)-(indole-3
-Yl) glyoxylamide Example 34: N- (pyridin-3-yl)-(indole-3-
Il) glyoxylamide.

──────────────────────────────────────────────────続 き Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 A61P 29/00 37/00 37/00 C07D 401/06 C07D 401/06 401/12 401/12 401/14 401 / 14 (72) Inventor Bernhard Kutcher Germany D-63477 Maintal 1 Stresemannstraße 9 (72) Inventor Peter Eich, Germany D-63486 Blue Fukebel Ludwig-Erhard Strasse 22 (72) Inventor Stephan Stelleny, Germany D-90571 Schwaig Handelstrasse 32 (72) Inventor Kai Brune, Germany D-91080 Marlo Fustein Weieruckerweek 17 (58) Fields studied (Int. Cl. ⁷ , DB name) ) C07D 209/18 C07D 401/06 C07D 401/12 C07D 401/14 CA (STN) REGISTRY (STN)

Claims (9)

(57) [Claims] (1) Formula I: Wherein the groups R, R ₁ , R ₂ , R ₃ , R ₄ and Z have the following meanings: R represents hydrogen, (C ₁ -C ₆ ) -alkyl, wherein the alkyl group is The phenyl ring itself may be substituted by one or more phenyl rings.
C ₁ -C ₆ - alkyl, C ₃ -C ₇ - by cycloalkyl, by carboxyl groups, C ₁ -C ₆ - alkanol esterified carboxyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, an ethoxy group , benzyloxy group and by one or more C ₁ -C in the phenyl moiety ₆ - alkyl group, optionally substituted by benzyl group substituted by a halogen atom or trifluoromethyl group, R ₁ is 1 or more the C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy, hydroxy, benzyloxy, nitro, amino, C ₁
-C ₆ - alkylamino, C ₁ ~C ₆ - alkoxycarbonyl by carbonyl amino or carboxyl group or a C ₁ -C ₆ - phenyl ring is substituted by alkanol esterified carboxyl group or a fluorine or formula II: Wherein the pyridine-skeleton is optionally linked at ring carbon atoms 2, 3, and 4,
_{May be} substituted by substituents R ₅ and R ₆ , wherein R ₅
And R ₆ may be the same or different and C ₁ -C ₆ −
Alkyl, C ₃ -C ₇ -cycloalkyl, C ₁ -C ₆ -alkoxy, nitro, amino, hydroxy, halogen and trifluoromethyl may be represented, furthermore, ethoxycarbonylamino- and carboxyalkoxy, where Wherein the alkyl group may have C-atoms 1-4, further R ₁ may represent an allylaminocarbonyl-2-methyl-prop-1-yl group, R ₂ represents a benzyl group Represents a phenyl ring in the benzyl group is a carboxyl group esterified with a C ₁ -C ₆ -alkanol by a halogen, a C ₁ -C ₆ -alkyl, a C ₃ -C ₇ -cycloalkyl, a carboxyl group, a trifluoromethyl group, a hydroxyl group, a methoxy group, may be substituted by an ethoxy group or a benzyl group, further, R ₂ is
2-, 3- and 4-pyridyl-methyl groups,
The pyridyl backbone, halogen, C ₁ -C ₄ - alkyl or C ₁ -C ₄ - may be substituted with an alkoxy group, R ₃ and R ₄ may be identical or different and are hydrogen,
Hydroxy, C ₁ -C ₆ - alkyl, C ₃ -C ₇ - cycloalkyl, C ₁ -C ₆ - alkanoyl, C ₁ -C ₆ - alkoxy, halogen and benzyloxy, further, a nitro group, an amino group,
C ₁ -C ₄ - mono- - or dialkyl-substituted amino group, C ₁ -C ₃ -
Alkoxy - carbonyl amino - group or a C ₁ -C ₃ - alkoxycarbonylamino -C ₁ -C ₃ - alkyl - group, Z is representative of a O] of N- substituted-indole-3-glyoxylamide or an acid addition salt. 2. The following compound according to claim 1, wherein N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -indol-3-yl) -glyoxylamide, N- (pyridine- 3-yl)-[1- (4-Fluorobenzyl) -indol-3-yl] -glyoxylamide, N- (pyridin-3-yl)-(1-benzylindol-3-yl) -glyoxylamide, N -(Pyridin-3-yl)-[1- (2-chlorobenzyl) -indol-3-yl] -glyoxylamide, N- (4-fluorophenyl)-[1- (4-fluorobenzyl) -indole- 3-yl] -glyoxylamide, N- (4-nitrophenyl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide, N- (2-chloro Pyridin-3-yl)-[1- (4-
Fluorobenzyl) -indol-3-yl] -glyoxylamido, N- (pyridin-4-yl)-(1-benzylindol-3-yl) -glyoxylamido, N- (pyridin-4-yl)-[1 -(3-pyridylmethyl) -indol-3-yl] -glyoxylamide, N- (4-fluorophenyl)-[1- (2-pyridylmethyl) -indol-3-yl] -glyoxylamide, N- ( 4-fluorophenyl)-[1- (3-pyridylmethyl) -indol-3-yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (4-chlorobenzyl) -indole-3- Yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (2-chlorobenzyl) -indol-3-yl] -glyoxylamide N- (pyridin-2-yl)-[1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (2-pyridylmethyl)- Indole-3-yl] -glyoxylamide, N- (pyridin-2-yl)-(1-benzyl-indol-3-yl) -glyoxylamide, N- (pyridin-4-yl)-[1- (4 -Fluorobenzyl) -6-ethoxycarbonylamino-indol-3-yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-ethoxycarbonylamino-indole-3 -Yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -6-cyclopentyloxycarbonylamido - indol-3-yl] - glyoxylamide, N-(3,4,5-trimethoxybenzyl) -N- (allyl aminocarbonyl-2-methyl - prop-l-yl) -
[1- (4-Fluorobenzyl) -indol-3-yl] -glyoxylamide, N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-methoxy-indol-3-yl] -Glyoxylamide, N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-hydroxy-indol-3-yl]-
Glyoxylamide, N- (pyridin-4-yl)-[1- (4-fluorobenzyl) -5-ethoxycarbonylamino-methyl-indol-3-yl] -glyoxylamide. 3. Use of a compound of formula I according to claims 1 and 2 for the manufacture of a medicament. 4. A compound of formula I according to claim 1, alone or mutually, for the manufacture of a medicament having an anti-asthma, anti-allergic and immunosuppressive / immunomodulating action. Use of combinations. 5. A compound of formula I according to claim 1, alone or for the manufacture of a medicament for transplantation and for the treatment of psoriasis, rheumatic diseases and chronic polyarthritis. Use in combination with each other. 6. A medicament comprising at least one compound of the formula I according to claim 1 or 2 together with customary carriers and / or diluents or auxiliaries. 7. A compound of formula I according to claim 1 or 2 together with conventional pharmacological carriers and / or diluents or other auxiliaries to form a pharmaceutical composition or a therapeutically active substance. A method for producing pharmaceuticals, characterized in that it can be used. 8. The medicament according to claim 6, in the form of tablets, dragees, capsules, solutions or ampoules, suppositories, ointments, powder compositions for inhalation use, suspensions, creams and ointments. 9. An N-substituted indole-3 of the formula I wherein R, R ₁ , R ₂ , R ₃ , R ₄ and Z have the meaning as defined in claim 1.
To produce glyoxylamide: a) Formula IV: Wherein R ₃ and R ₄ have the meaning given above, in a protic, dipolar, aprotic or non-polar organic solvent, added to the suspended base and the group R Reacting with a reactive compound R ₂ -halogen having ₂ and a halogen as a leaving group, wherein R ₂ is as defined above,
V: Wherein R ₂ , R ₃ and R 4 are as defined above, in an aprotic or non-polar organic solvent, in a non-protic or non-polar organic solvent of the formula VI: (C—Z-Hal) ₂ VI [ In the formula, Z represents oxygen, Hal is halogen fluorine, chlorine,
With a reactive compound of the formula VII: HNRR ₁ VII, wherein R and R ₁ are as defined above, and an aprotic compound Or reacting in a dipolar, aprotic solvent to isolate the desired compound of formula I or b) formula IV: Wherein R ₃ and R ₄ represent the same as defined above in an aprotic or non-polar solvent in a solvent of the formula VI: (C—Z—Hal) ₂ VI wherein Z is oxygen Hal represents halogen fluorine, chlorine,
With bromine or iodine], and then in an aprotic or dipolar aprotic solvent of the formula VII: HNRR ₁ VII wherein R and R ₁ are as defined above. With a primary or secondary amine of the formula VIII Wherein R, R ₁ , R ₃ , R ₄ and Z are as defined above, in a protic, dipolar, aprotic or non-polar organic solvent. Reacting in the presence of a suspended base with a reactive compound R ₂ -halogen having a group R ₂ and a halogen as leaving group, wherein R ₂ is as defined above, to give the desired compound of formula I A process for preparing an N-substituted indole-3-glyoxylamide of the formula I according to claim 1 or 2, characterized in that: